Total calorie restricted diets dramatically decrease the incidence of spontaneous tumors in strains of mice with a high incidence of murine mammary tumor virus (MuMTV) induced mammary cancer. Since the development of mammary tumors in mice result from an interplay of MuMTV, hormones and the immune system, we propose to study the effect of restricted calorie intake on each of these factors in various mouse strains. In these studies we will use C3H, GR, GRf and RIII mice which have a high incidence of naturally-occurring mammary tumors. Mice from strains with a low incidence of mammary tumors (C57BL, BALB/c) will also be used and will be exogenously infected with MuMTV or given agents which normally enhance tumorigenesis, such as hormones or chemical carcinogens. The effect of calorie restriction on the mammary tumor incidence in all strains of mice will be determined and expression of MuMTV in these mice will be monitored by electron microscopic, immunological and biochemical techniques. We will also determine if hormone receptors or the levels of circulating hormones that are important to mammary gland and tumor development are altered as a result of dietary restriction. Since calorie restriction may prevent the progression of preneoplastic nodules (HANs) in mice to malignant tumors, we will transplant HANs into MuMTV-producing or non-producing syngeneic mice fed normal or restricted diets in order to determine if hormones and/or viral expression affect the progression of HANs to tumors. In vitro organ culture of mammary glands in the presence of hormones and/or virus prior to transplantation will be used to determine how these factors affect the transformation of HANs into tumors. We will also examine the way in which diet affects the humoral and cellular immune response of both high and low tumor incidence strains of mice. As a result of these investigations, we hope to understand the mechanism by which the interaction between MuMTV, hormones, and the immune response may be altered by diet in such a way as affect murine mammary tumorigenesis.